3-Fluorocinnamic acid (I) is activated as the mixed anhydride (II) with pivaloyl chloride and subsequently coupled to the lithium anion of (S)-4-benzyloxazolidin-2-one (III) to provide the N-acyl oxazolidinone (IV). Cycloaddition of the cinnamoyl derivative (IV) with N-methoxymethyl-N-trimethylsilylmethyl benzylamine (V) in the presence of trifluoroacetic acid gives rise to a diastereomeric mixture of trans-pyrrolidines (VI) and (VII), separable by column chromatography. The desired isomer (VII) is then reduced by LiAlH4 to alcohol (VIII), which is further protected as the silyl ether (IX). Debenzylation of (IX) by transfer hydrogenolysis with ammonium formate and Pearlman's catalyst furnishes pyrrolidine (X).
Condensation of oxalyl chloride (XI) with N,O-dimethylhydroxylamine produces N,N'-dimethyl-N,N'-dimethoxy oxamide (XII). This is then condensed with cyclobutylmethylmagnesium bromide (XIII) to afford the ketoamide (XIV). Asymmetric keto group reduction employing (R)-alpine borane leads to the (S)-alcohol (XV) in 91% enantiomeric excess. Hydrolysis of the N-methoxyamide function of (XV) to provide hydroxyacid (XVI) is then accomplished employing potassium tert-butoxide in the presence of the equimolecular amount of H2O in THF. Alkylation of hydroxyacid (XVI) with benzyl bromide and Et3N furnishes the corresponding benzyl ester (XVII). Treatment of (XVII) with trifluoromethanesulfonic anhydride gives rise to triflate (XVIII), which is further condensed with pyrrolidine (X) to produce (XIX). After desilylation of (XIX) with tetrabutylammonium fluoride, the resultant alcohol (XX) is oxidized to aldehyde (XXI) under Swern conditions.
Reductive amination of N-Boc-4-piperidone (XXII) with benzylamine, followed by benzyl group hydrogenolysis of the resultant secondary amine (XXIII) gives rise to N-Boc-4-aminopiperidine (XXIV). This is then condensed with 2-chloro-5-trifluoromethylpyrimidine (XXV) to furnish adduct (XXVI). Subsequent alkylation of amine (XXVI) with allyl bromide in the presence of sodium hexamethyldisilazide affords the N-allyl amine (XXVII), which is further hydrogenated to the N-propyl analogue (XXVIII). Acidic hydrolysis of (XXVIII) then removes the N-Boc protecting group, providing piperidine (XXIX). (1,2)
Catalytic hydrogenolysis of the benzyl ester (XXI) affords the carboxylic acid (XXX). The aldehyde-acid (XXX) is then reductively aminated with piperidine (XXIX) in the presence of NaBH(OAc)3 to produce the title compound. (1,2)